The risk of discontinuation of oral anticoagulant therapy (both warfarin and direct oral anticoagulant therapies [DOACs]) among nonvalvular atrial fibrillation patients was high. Although the hazard ratio for discontinuation favors DOACs, it is unlikely that the small difference in discontinuation relative to warfarin is clinically meaningful.

ABSTRACT

Objectives: To identify factors associated with all-cause discontinuation (patient discontinued on their own or physician discontinuation) of oral anticoagulants (OACs) among nonvalvular atrial fibrillation (NVAF) patients.

Study Design: Retrospective cohort study.

Methods: We analyzed the MarketScan claims database from October 2009 to July 2012. Adult patients were eligible if they newly initiated an OAC in the study period, had an atrial fibrillation diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 427.31 or 472.32), and had at least 6 months of continuous enrollment after OAC initiation. Multivariable Cox proportional hazards regression was used to assess factors associated with discontinuation. Adjusted hazard ratios (HRs) and 95% CIs were reported.

Conclusions: The risk of independent discontinuation of OAC treatment among NVAF patients was high. Patients on DOACs compared with warfarin and those with several comorbid conditions had significantly lower risk of discontinuation, while those with prior bleeding were more likely to discontinue.

Am J Manag Care. 2016;22(1):e1-e8

Take-Away Points

As market experience with direct oral anticoagulant therapies (DOACs) grows, it is important to understand the real-world treatment patterns for stroke prevention in patients with atrial fibrillation (AF).

Our study shows that the risk of discontinuation from any cause of OAC therapy among patients with nonvalvular AF was high.

Atrial fibrillation (AF) is the most common cardiac arrhythmia seen in clinical practice and is becoming a growing public health concern. Although the magnitude of future trends cannot be definitively predicted, current research indicates that the disease’s incidence and prevalence will gradually increase. Go et al estimated in 2001 that approximately 2.3 million adults in the United States currently had AF, and projected an increase to more than 5.6 million by the year 2050 with more than 50% of affected individuals 80 years or older.1 Colilla et al reported projections in 2013 that AF incidence will increase from 1.2 million in 2010 to 2.6 million in 2030, with the prevalence estimates increasing from 5.2 million in 2010 to 12.1 million in 2030.2 In 2006, Miyaska et al reported the estimated prevalence to be more than 10 million by 2050.3

AF results in a 4- to 5-fold increase in the risk of stroke and thromboembolic events, accounting for approximately 15% of all strokes reported in the United States.1,4,5 In addition, AF has been associated with increased risk of heart failure, cognitive dysfunction, left ventricular dysfunction, and death.3,6 AF has enormous socioeconomic implications because, in addition to increasing medical costs and economic burden on the healthcare system, it can lead to a reduction in patients’ quality of life (QOL) and functional status.1,7-10 Coyne et al reported that the total annual medical costs for treatment of AF were approximately $6.65 billion in 2005 dollars.11 Kim et al reported that the national incremental AF cost was between $6 and $26 billion in 2008 dollars.12 The economic burden of stroke in the United States for 2008 was estimated at $65.5 billion, whereas the annual estimates for the 27 European Union countries and the United Kingdom were €27 billion and £8.9 billion, respectively, in 2008.7,8 The QOL of patients with AF has been reported to be significantly poorer compared with the general population, as well as with patients with coronary heart disease.9

Historically, stroke-prevention guidelines for AF patients recommended aspirin or no therapy for those with an otherwise low stroke risk, and an oral anticoagulant (OAC) for moderate- to high-risk patients.4,13-15 With the recent adoption of the CHA2DS2-VASc score prediction rule, the number of patients recommended for OAC therapy has dramatically increased compared with those previously recommended under the CHADS2 system. Many patients, especially women 75 years or older (now + 2 from + 1 in CHADS2), have been reclassified as high- rather than low-risk, and OAC use has therefore significantly increased. It has increased even in those still classified as low risk.16

For several decades, warfarin has been the primary OAC used for stroke prevention in AF. While highly effective for preventing stroke in AF patients, its significant drawbacks include variable dose requirements and numerous dietary and medication interactions, as well as a commitment to lifelong, regular, frequent monitoring of the patient’s international normalized ratio (INR) to ensure it is within the recommended range.4,17-19 As a result, warfarin is associated with relatively frequent bleeding complications, resulting in a high proportion of patients discontinuing therapy (all-cause, initiated by either the patient or their doctor) or receiving suboptimal therapy in usual clinical practice.4,17-21

In recent years, 3 direct oral anticoagulants (DOACs)—dabigatran, rivaroxaban, and apixaban—have been approved in the United States for stroke prevention in nonvalvular AF (NVAF). In clinical trials, all 3 were shown to be safe and effective compared with warfarin.22-24 These new agents have advantages over warfarin because their use doesn’t require regular INR monitoring and they have fewer drug and food interactions. Recently published guidelines have also recommended the use of DOACs as alternatives to the conventional therapy (vitamin K antagonists or antiplatelet agents) in most NVAF patients requiring stroke prevention.4

Few studies have shown treatment discontinuation over time in the warfarin-treated patients.20 However, it is absolutely essential to evaluate in detail the treatment patterns and the risk of discontinuation among NVAF patients in the real world, as well as to identify predictors of discontinuation. Although evidence exists for some rationales for discontinuation in warfarin-treated patients, such as bleeding complications,4,17-20 little comparable information exists for DOAC-treated patients. Compared with warfarin, DOACs have a shorter half-life; therefore, if the drug is discontinued, noncompliance can result in the anticoagulation effect coming to a halt and thrombosis ensuing.25-27 It is thus critical to understand real-world discontinuation patterns, including the reasons for discontinuation, for warfarin and DOACs.

Currently, however, little literature exists on recent real-world treatment patterns among AF patients on DOACs. A recent observational study in 70 patients starting on dabigatran (median treatment duration was 140.5 days) reported a discontinuation rate of 10%; 77% of these patients reported treatment satisfaction with dabigatran, although 79% of those previously treated with warfarin preferred dabigatran.28 Another early real-world study on dabigatran adherence in 103 patients reported that only 12% had inadequate adherence. Rivaroxaban and apixaban were approved after dabigatran, and we identified no studies that reported real-world treatment patterns with these drugs.29 As market experience with DOACs grows, it is important to understand the real-world treatment patterns for stroke prevention in patients with AF. The goals of this study were to assess the risk of discontinuation among AF patients on OACs (including DOACs) and to identify factors associated with such discontinuation.

METHODS

A retrospective cohort study was conducted using the Truven Health MarketScan Research Databases from October 2009 to July 2012. Patients were eligible if: they newly initiated an OAC (warfarin, dabigatran, or rivaroxaban) in the study period, were 18 years or older at the time of treatment initiation, had at least 1 diagnosis of AF in the 12 months prior to treatment initiation (identified by any medical claim associated with an International Classification of Diseases, Ninth Revision, Clinical Modification code of 427.31 [AF] or 427.32 [atrial flutter]), and had at least 6 months of continuous enrollment (ie, continuous health insurance coverage) after OAC initiation and continuous enrollment in the plan for 12 months prior to study entry. Patients were excluded if they had valvular heart disease, cardiac surgery during the 12-month pre-index period, or used any OAC treatment (warfarin or DOAC) in the 12 months prior to study entry. The index date was defined as date of first OAC prescription after an AF diagnosis during the study eligibility period, and the baseline period was the 12 months prior to index date. The index prescription was defined as the first OAC prescribed in the study period (warfarin, dabigatran, rivaroxaban).

The DOACs included in this study were dabigatran and rivaroxaban, because apixaban was approved in December 2012, after the study’s end date. Figures 1 and 2 show the study schematics and the flow chart for patient selection, respectively. Patients were followed until 1 of the following events, whichever earliest, occurred: an interruption in continuous enrollment, a switch or a discontinuation of index treatment, or the end of the study. Discontinuation was defined as having no claims for the index OAC prescription within 60 days of the final day’s supply of the last filled prescription for the index OAC. Patients who received a prescription for an OAC other than the index OAC prescription during the follow-up period were considered switchers, and were thus excluded.

Statistical Analysis

The absolute rate of discontinuation of OAC therapy was determined; additionally, time to discontinuation (in days) and the length of follow-up (in days) were calculated. Patients were censored on the date of discontinuation, end of study period, or interruption in continuous enrollment—whichever occurred earliest. Multivariable Cox proportional hazards regression analysis was conducted to assess the clinical and demographic factors associated with discontinuation in warfarin initiators and DOAC initiators. Hazard ratios (HRs) and the corresponding 95% CIs were calculated. Demographic factors such as insurance type and geographic region, as well as clinical characteristics from the 12-month baseline period—such as bleeds, stroke, deep vein thrombosis, pulmonary embolism (PE), diabetes, hypertension, myocardial infarction, dyspepsia, renal disease, and congestive heart failure (CHF)—were included. All analyses were done using SAS version 9.3 (SAS Institute, Cary, North Carolina) and STATA version 13 (STATACorp, College Station, Texas).

RESULTS

A total of 11,825 patients with diagnosis from October 2009 to July 2012 were available for the analyses. Table 1 presents the baseline demographics and baseline comorbidities. A total of 5598 (47.34%) NVAF patients discontinued treatment with OACs. The majority of the total population of patients was 65 years or older (55.07%) and male (59.5%). The most common comorbidities were hypertension (42.62%), diabetes (15.29%), CHF (14.83%), and coronary artery disease (14.67%).